Anticholinergics which may be used as medicaments as well as processes for preparing them

ABSTRACT

The present invention relates to new anticholinergics of general formula 1  
                 
 
     wherein A, X − , and the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  may have the meanings given in the claims and in the specification, processes for preparing them and their use as pharmaceutical compositions.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.09/976,950, for which priority is claimed. Furthermore, benefit of U.S.Provisional Application Serial No. 60/252,777, filed on Nov. 22, 2000 ishereby claimed. Moreover, each of these applications is incorporated byreference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to new anticholinergics of generalformula 1

[0003] wherein A, X⁻, and the groups R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ mayhave the meanings given in the claims and specification, processes forpreparing them as well as their use as medicaments.

BACKGROUND OF THE INVENTION

[0004] Anticholinergics may be used to therapeutic effect in a widerange of illnesses. Special mention should be made, for example, of thetreatment of asthma or chronic obstructive pulmonary disease (COPD). Fortreating these complaints, WO 92/16528 proposes anticholinergics whichhave a scopine, tropenol or tropine basic structure.

[0005] The underlying objective of WO 92/16528 is the preparation ofanticholinergically effective compounds which are characterized by theirlong-lasting activity. To achieve this aim, WO 92/16528 discloses, interalia, benzilic acid esters of scopine, tropenol, or tropine.

[0006] For treating chronic diseases, it is often desirable to preparemedicaments with a longer duration of activity. As a rule, this ensuresthat the concentration of the active substance in the body needed toachieve the therapeutic effect is guaranteed for a longer period withoutthe need to re-administer the drug at frequent intervals. Moreover,giving an active substance at longer time intervals contributes to thewellbeing of the patient to a high degree. It is particularly desirableto prepare a pharmaceutical composition which can be usedtherapeutically by administration once a day (single dose). The use of adrug once a day has the advantage that the patient can become accustomedrelatively quickly to regularly taking the drug at certain times of theday.

[0007] In order to be used as a medicament taken once a day, the activesubstance to be given must meet particular requirements. First of all,the onset of the desired activity should take place relatively quicklyafter administration of the drug and ideally should have as constant aneffect as possible over a subsequent fairly long period of time. On theother hand, the duration of activity of the drug should notsubstantially exceed a period of about one day. Ideally, an activesubstance has an activity profile such that the preparation of a drugfor administration once a day, which contains the active substance intherapeutically beneficial doses, can be deliberately controlled.

[0008] It has been found that the benzilic acid esters of scopine,tropenol, and tropine disclosed in WO 92/16528 do not meet thesestringent requirements. Because of their extremely long period ofactivity, which significantly exceeds the above-mentioned period ofabout one day, they cannot be used therapeutically for administration ina single dose per day.

[0009] The aim of the present invention is therefore to provide newanticholinergics which, by virtue of their activity profile, make itpossible to prepare a drug for administration once a day. A furtherobjective of the invention is to prepare compounds characterized by arelative rapid onset of activity. The invention further sets out toprovide compounds which, after a rapid onset of activity, have asconstant an activity as possible over a subsequent lengthy period oftime. A further aim of the invention is to provide compounds whoseduration of activity does not substantially exceed a period of about oneday in therapeutically beneficial doses. Finally, the invention sets outto provide compounds which have an activity profile which ensures goodcontrol of the therapeutic effect (i.e., total therapeutic effectwithout side effects caused by a build-up of the substance in the body).

DETAILED DESCRIPTION OF THE INVENTION

[0010] Surprisingly, it has been found that the above objectives areachieved by means of compounds of general formula 1 wherein the group R⁷does not denote hydroxy.

[0011] Accordingly the present invention relates to compounds of generalformula 1

[0012] wherein:

[0013] A denotes a double-bonded group selected from among

[0014] X⁻ denotes an anion with a single negative charge,

[0015] R¹ and R² denote C₁-C₄-alkyl, which may optionally be substitutedby hydroxy or halogen;

[0016] R³, R⁴, R⁵, and R⁶, which may be identical or different, denotehydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF₃, CN, NO₂, orhalogen;

[0017] R⁷ denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy,C₁-C₄-alkylene-halogen, halogen-C₁-C₄-alkyloxy, C₁-C₄-alkylene-OH, CF₃,—C₁-C₄-alkylene-C₁-C₄-alkyloxy, —O—COC₁-C₄-alkyl,—O—COC₁-C₄-alkyl-halogen, —O—COCF₃, or halogen,

[0018] while if A denotes

[0019] R¹ and R² denote methyl, and R³, R⁴, R⁵, and R⁶ denote hydrogen,R⁷ cannot also be hydrogen.

[0020] Preferred compounds of general formula 1 are those wherein:

[0021] A denotes a double-bonded group selected from among

[0022] X⁻ denotes an anion with a single negative charge selected fromamong chloride, bromide, methylsulfate, 4-toluenesulfonate, andmethanesulfonate, preferably bromide;

[0023] R¹ and R², which may be identical or different, denote a groupselected from among methyl, ethyl, n-propyl and isopropyl, which mayoptionally be substituted by hydroxy or fluorine, preferablyunsubstituted methyl;

[0024] R³, R⁴, R⁵, and R⁶, which may be identical or different, denotehydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine,chlorine, bromine, CN, CF₃, or NO₂; and

[0025] R⁷ denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, —CH₂—F,—CH₂—CH₂—F, —O—CH₂—F, —O—CH₂—CH₂—F, —CH₂—OH, —CH₂—CH₂—OH, CF₃, —CH₂—OMe,—CH₂—CH₂—OMe, —CH₂—OEt, —CH₂—CH₂—OEt, —O—COMe, —O—COEt, —O—COCF₃,—O—COCF₃, fluorine, chlorine, or bromine.

[0026] Particularly preferred are compounds of general formula 1,wherein:

[0027] A denotes a double-bonded group selected from among:

[0028] X⁻ denotes an anion with a single negative charge selected fromamong chloride, bromide and methanesulfonate, preferably bromide;

[0029] R¹ and R², which may be identical or different, denote a groupselected from methyl and ethyl, which may optionally be substituted byhydroxy or fluorine, preferably unsubstituted methyl;

[0030] R³, R⁴, R⁵, and R⁶, which may be identical or different, denotehydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine,chlorine, or bromine; and

[0031] R⁷ denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF₃, orfluorine.

[0032] Preferred compounds of general formula 1 according to theinvention are those wherein:

[0033] A denotes a double-bonded group selected from among

[0034] X⁻ denotes bromide;

[0035] R¹ and R², which may be identical or different, denote a groupselected from methyl and ethyl, preferably methyl;

[0036] R³, R⁴, R⁵, and R⁶, which may be identical or different, denotehydrogen, methyl, methyloxy, chlorine, or fluorine; and

[0037] R⁷ denotes hydrogen, methyl or fluorine.

[0038] Of particular importance according to the invention are compoundsof general formula 1, wherein:

[0039] A denotes a double-bonded group selected from among

[0040] X⁻ denotes bromide;

[0041] R¹ and R² which may be identical or different denote methyl orethyl, preferably methyl;

[0042] R³, R⁴, R⁵, and R⁶, which may be identical or different, denotehydrogen or fluorine, preferably hydrogen; and

[0043] R⁷ denotes hydrogen, methyl or fluorine, preferably methyl orfluorine, most preferably methyl.

[0044] The invention relates to the compounds of formula 1, optionallyin the form of the individual optical isomers, mixtures of theindividual enantiomers or racemates thereof.

[0045] In the compounds of general formula 1, the groups R³, R⁴, R⁵, andR⁶, provided that they do not denote hydrogen, may each be in the ortho,meta, or para-position relative to the bond to the “—C—R⁷” group.Provided that none of the groups R³, R⁴, R⁵, and R⁶ denotes hydrogen, R³and R⁵ are preferably linked in the para-position and R⁴ and R⁶ arepreferably linked in the ortho- or meta-position, most preferably in themeta-position. If one of the groups R³ and R⁴ and one of the groups R⁵and R⁶ denotes hydrogen, the other group in each case is preferablylinked in the meta- or para-position, most preferably in thepara-position. If none of the groups R³, R⁴, R⁵, and R⁶ denoteshydrogen, according to the invention the compounds of general formula 1wherein the groups R³, R⁴, R⁵, and R⁶ have the same meaning areparticularly preferred.

[0046] Of particular importance according to the invention are thecompounds of general formula 1 wherein the ester-substituent on thenitrogen-bicyclic group is in the α-configuration. These compoundscorrespond to general formula 1-α

[0047] According to the invention, the following compounds are ofparticular importance: tropenol 2,2-diphenylpropionate-methobromide;scopine 2,2-diphenylpropionate-methobromide; scopine2-fluoro-2,2-diphenylacetate-methobromide; and tropenol2-fluoro-2,2-diphenylacetate-methobromide.

[0048] Unless otherwise stated, the alkyl groups are straight-chained orbranched alkyl groups having 1 to 4 carbon atoms. The following arementioned by way of example: methyl, ethyl, propyl or butyl. In somecases the abbreviations Me, Et, Prop, or Bu are used to denote thegroups methyl, ethyl, propyl, or butyl. Unless otherwise stated, thedefinitions propyl and butyl include all the possible isomeric forms ofthe groups in question. Thus, for example, propyl includes n-propyl andisopropyl, butyl includes isobutyl, sec-butyl, and tert-butyl, etc.

[0049] Unless otherwise stated, the alkylene groups are branched andunbranched double-bonded alkyl bridges having 1 to 4 carbon atoms. Thefollowing are mentioned by way of example: methylene, ethylene,propylene or butylene.

[0050] Unless otherwise stated, the alkylene-halogen groups are branchedand unbranched double-bonded alkyl bridges having 1 to 4 carbon atomswhich are mono-, di-, or trisubstituted, preferably monosubstituted, bya halogen. Accordingly, unless otherwise stated, the alkylene-OH groupsare branched and unbranched double-bonded alkyl bridges having 1 to 4carbon atoms which are mono-, di-, or trisubstituted, preferablymonosubstituted, by a hydroxy.

[0051] Unless otherwise stated, the term alkyloxy groups denotesbranched and unbranched alkyl groups having 1 to 4 carbon atoms whichare linked via an oxygen atom. Examples of these include: methyloxy,ethyloxy, propyloxy, or butyloxy. The abbreviations MeO-, EtO-, PropO-,or BuO- are used in some cases to denote the groups methyloxy, ethyloxy,propyloxy, or butyloxy. Unless otherwise stated, the definitionspropyloxy and butyloxy include all possible isomeric forms of the groupsin question. Thus, for example, propyloxy includes n-propyloxy andisopropyloxy, butyloxy includes isobutyloxy, secbutyloxy, andtert-butyloxy, etc. In some cases, within the scope of the presentinvention, the term alkoxy is used instead of the term alkyloxy.Accordingly, the terms methoxy, ethoxy, propoxy, or butoxy may also beused to denote the groups methyloxy, ethyloxy, propyloxy, or butyloxy

[0052] Unless otherwise stated, the term alkylene-alkyloxy groupsdenotes branched and unbranched double-bonded alkyl bridges having 1 to4 carbon atoms which are mono-, di-, or trisubstituted, preferablymonosubstituted, by an alkyloxy group.

[0053] Unless otherwise stated, the term —O—CO-alkyl groups denotesbranched and unbranched alkyl groups having 1 to 4 carbon atoms whichare linked via an ester group. The alkyl groups are linked directly tothe carbonyl carbon of the ester group. The term —O—CO-alkyl-halogengroup should be understood in the same way. The group —O—CO—CF₃ denotestrifluoroacetate.

[0054] Halogen within the scope of the present invention denotesfluorine, chlorine, bromine, or iodine. Unless stated otherwise,fluorine and bromine are the preferred halogens. The group CO denotes acarbonyl group.

[0055] The compounds according to the invention may partly be prepared,as illustrated below, analogously to procedures which are already knownfrom the prior art (Diagram 1). The carboxylic acid derivatives offormula 3 are known in the art or may be obtained using methods ofsynthesis known in the art. If only suitably substituted carboxylicacids are known in the art, the compounds of formula 3 may also beobtained directly from them by acid- or base-catalyzed esterificationwith the corresponding alcohols or by halogenation with thecorresponding halogenation reagents.

[0056] Starting from the compounds of formula 2 the esters of generalformula 4 may be obtained by reacting the carboxylic acid derivatives offormula 3, wherein R may denote chlorine or a C₁-C₄-alkyloxy group, forexample. When R denotes C₁-C₄-alkyloxy, this reaction may be carriedout, for example, in a sodium melt at elevated temperature, preferablyat about 50° C.-150° C., most preferably at about 90° C.-100° C. at lowpressure, preferably below 500 mbar, most preferably below 75 mbar.Alternatively, instead of the derivatives 3 wherein R denotesC₁-C₄-alkyloxy, the corresponding acid chlorides (where R is Cl) may beused.

[0057] The compounds of formula 4 thus obtained may be converted intothe target compounds of formula 1 by reacting the compounds R²—X,wherein R² and X may be as hereinbefore defined. This synthesis step mayalso be carried out analogously to the examples of synthesis disclosedin WO 92/16528.

[0058] Alternatively to the procedure illustrated in Diagram 1 forsynthesizing the compounds of formula 4, the derivatives 4 in which thenitrogen bicyclic group is a scopine derivative may be obtained byoxidation (epoxidation) of compounds of formula 4 wherein thenitrogen-bicyclic group is a tropenyl group. This may be done asfollows, according to the invention.

[0059] Compound 4, wherein A denotes —CH═CH—, is suspended in a polarorganic solvent, preferably in a solvent selected from amongN-methyl-2-pyrrolidone (NMP), dimethylacetamide, and dimethylformamide,preferably dimethylformamide, and then heated to a temperature of about30° C. to 90° C., preferably 40° C. to 70° C. Then a suitable oxidizingagent is added and the mixture is stirred at constant temperature for 2hours to 8 hours, preferably 3 hours to 6 hours. The preferred oxidizingagent is vanadium pentoxide mixed with H₂O₂, most preferably H₂O₂-ureacomplex combined with vanadium pentoxide. The mixture is worked up inthe usual way. The products may be purified by crystallization orchromatography, depending on their crystallization tendencies.

[0060] Alternatively, the compounds of formula 4 wherein R⁷ denoteshalogen may also be obtained by the method shown in Diagram 2.

[0061] For this, the benzilic acid esters of formula 5 are converted,using suitable halogenating reagents, into the compounds 4 wherein R⁷denotes halogen. The reaction of halogenation to be carried outaccording to Diagram 2 is already sufficiently well known in the art.

[0062] The benzilic acid esters of formula 5 may be obtained inaccordance with or analogously to methods known in the art (see, e.g.,WO 92/16528).

[0063] As shown in Diagram 1, the intermediate products of generalformula 4 are of crucial importance. Accordingly, in another aspect, thepresent invention relates to the intermediates of formula 4

[0064] wherein:

[0065] A denotes a double-bonded group selected from among:

[0066] R¹ denotes C₁-C₄-alkyl, which may optionally be substituted byhydroxy or halogen;

[0067] R³, R⁴, R⁵, and R⁶, which may be identical or different, denotehydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF₃, CN, NO₂, orhalogen;

[0068] R⁷ denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy,C₁-C₄-alkylene-halogen, halogen-C₁-C₄-alkyloxy, C₁-C₄-alkylene-OH, CF₃,—C₁-C₄-alkylene-C₁-C₄-alkyloxy, —O—COC₁-C₄-alkyl,—O—COC₁-C₄-alkyl-halogen, —O—COCF₃, or halogen,

[0069] while if A denotes

[0070] R¹ denotes methyl, and R³, R⁴, R⁵, and R⁶ denote hydrogen, R⁷cannot be n-propyl.

[0071] Preferred are compounds of general formula 4, wherein:

[0072] A denotes a double-bonded group selected from among:

[0073] R¹ denotes a group selected from among methyl, ethyl, n-propyland isopropyl, which may optionally be substituted by hydroxy orfluorine, preferably unsubstituted methyl;

[0074] R³, R⁴, R⁵, and R⁶, which may be identical or different, denotehydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine,chlorine, bromine, CN, CF₃, or NO₂; and

[0075] R⁷ denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, —CH₂—F,—CH₂—CH₂—F, —O—CH₂—F, —O—CH₂—CH₂—F, —CH₂—OH, —CH₂—CH₂—OH, CF₃, —CH₂—OMe,—CH₂—CH₂—OMe, —CH₂—OEt, —CH₂—CH₂—OEt, —O—COMe, —O—COEt, —O—COCF₃,—O—COCF₃, fluorine, chlorine, or bromine.

[0076] Particularly preferred are compounds of general formula 4,wherein:

[0077] A denotes a double-bonded group selected from among:

[0078] R¹ denotes a group selected from methyl and ethyl, which mayoptionally be substituted by hydroxy or fluorine, preferablyunsubstituted methyl;

[0079] R³, R⁴, R⁵, and R⁶, which may be identical or different, denotehydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine,chlorine, or bromine; and

[0080] R⁷ denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF₃, orfluorine.

[0081] Preferred compounds of general formula 4 according to theinvention are those wherein

[0082] A denotes a double-bonded group selected from among:

[0083] R¹ denotes a group selected from methyl and ethyl, preferablymethyl;

[0084] R³, R⁴, R⁵, and R⁶, which may be identical or different, denotehydrogen, methyl, methyloxy, chlorine, or fluorine; and

[0085] R⁷ denotes hydrogen, methyl, or fluorine.

[0086] Of particular importance according to the invention are compoundsof general formula 4, wherein:

[0087] A denotes a double-bonded group selected from among

[0088] R¹ denotes methyl or ethyl, preferably methyl;

[0089] R³, R⁴, R⁵, and R⁶, which may be identical or different, denotehydrogen or fluorine, preferably hydrogen; and

[0090] R⁷ denotes hydrogen, methyl, or fluorine, preferably methyl orfluorine, most preferably methyl.

[0091] As in the compounds of general formula 1, in the intermediates offormula 4, the groups R³, R⁴, R⁵, and R⁶, provided that they do notdenote hydrogen, may each be in the ortho, meta, or para-positionrelative to the bond to the “—C—R⁷” group. Provided that none of thegroups R³, R⁴, R⁵, and R⁶ denotes hydrogen, R³ and R⁵ are preferablylinked in the para-position and R⁴ and R⁶ are preferably linked in theortho- or meta-position, most preferably in the meta-position. If one ofthe groups R³ and R⁴ and one of the groups R⁵ and R⁶ denotes hydrogen,the other group in each case is preferably linked in the meta- orpara-position, most preferably in the para-position. If none of thegroups R³, R⁴, R⁵, and R⁶ denotes hydrogen, according to the inventionthe intermediates of general formula 1 wherein the groups R³, R⁴, R⁵,and R⁶ have the same meaning are particularly preferred.

[0092] The examples of synthesis described hereinafter serve toillustrate the present invention still further. However, they areintended only as examples of procedures as an illustration of theinvention without restricting the invention to the subject-matterdescribed by way of example.

EXAMPLE 1 Scopine 2,2-diphenylpropionate Methobromide

[0093]

[0094] 1.1.: 2,2-diphenylpropionic Acid Chloride 3a

[0095] 52.08 g (0.33 mol) of oxalyl chloride are slowly added dropwiseto a suspension of 25.0 g (0.11 mol) of 2,2-diphenylpropionic acid, 100mL of dichloromethane, and 4 drops of dimethylformamide at 20° C. Themixture is stirred for 1 hour at 20° C. and 0.5 hours at 50° C. Thesolvent is distilled off and the residue remaining is used in the nextstep without any further purification.

[0096] 1.2.: Scopine 2,2-diphenylpropionate 4a

[0097] The residue obtained in step 1.1. is dissolved in 100 mLdichloromethane and at 40° C. a solution of 51.45 g (0.33 mol) ofscopine in 200 mL dichloromethane is added dropwise. The resultingsuspension is stirred for 24 hours at 40° C., then the precipitateformed is suction filtered and the filtrate is acidically extractedfirst with water, then with aqueous hydrochloric acid. The combinedaqueous phases are made alkaline with aqueous sodium carbonate solution,extracted with dichloromethane, the organic phase is dried over Na₂SO₄,evaporated to dryness, and the hydrochloride is precipitated from theresidue. The product is purified by recrystallization from acetonitrile.Yield: 20.85 g (47% of theory); TLC: R_(f) value: 0.24 (eluent:sec-butanol/formic acid/water 75:15:10); melting point: 203° C.-204° C.

[0098] 1.3: Scopine 2,2-diphenylpropionate Methobromide

[0099] 11.98 g (0.033 mol) of 4a, 210 mL of acetonitrile, 70 mL ofdichloromethane, and 20.16 g (0.1 mol) of 46.92% bromomethane inacetonitrile are combined at 20° C. and left to stand for 3 days. Thesolution is evaporated to dryness and the residue recrystallized fromisopropanol. Yield: 11.34 g (75% of theory); melting point: 208° C.-209°C.; C₂₄H₂₈NO₃xBr (458.4); elemental analysis: calculated: C (62.89), H(6.16), N (3.06); found: C (62.85), H (6.12), N (3.07).

EXAMPLE 2 Sconine 2-fluoro-2,2-diphenylacetate Methobromide

[0100]

[0101] 2.1: Scopine Benzilate 5a

[0102] The preparation of scopine benzilate is known in the art. It isdescribed in WO 92/16528.

[0103] 2.2: scopine 2-fluoro-2,2-diphenylacetate 4b

[0104] 2.66 g (0.02 mol) of dimethylaminosulfur trifluoride are cooledto 0° C. in 10 mL of dichloromethane and a solution of 5.48 g (0.015mol) of scopine benzilate 5a in 100 mL of dichloromethane is addeddropwise. Then the mixture is stirred for a further 30 minutes at 0° C.and 30 minutes at 20° C. While cooling, the solution is combined withwater, NaHCO₃ is added (to pH 7-8), and the organic phase is separatedoff. The aqueous phase is extracted with dichloromethane, the combinedorganic phases are washed with water, dried over Na₂SO₄, and evaporatedto dryness. The hydrochloride is precipitated from the residue andrecrystallized from acetonitrile. Yield: 6.90 g (85% of theory); meltingpoint: 227° C.-230° C.

[0105] 2.3: Scopine 2-fluoro-2,2-diphenylacetate Methobromide

[0106] 2.88 g (0.0078 mol) of the free base of scopine benzilate arereacted analogously to the procedure in step 1.3. The product ispurified by recrystallization from isopropanol. Yield: 2.62 g (73% oftheory); TLC: R_(f) value: 0.31 (eluent as in step 1.2); melting point:130° C.-134° C.

EXAMPLE 3 Tropenol 2,2-diphenylpropionate Methobromide

[0107]

[0108] 3.1.: methyl 2,2-diphenylpropionate 3b

[0109] 37.60 g (0.247 mol) of DBU are added dropwise to a suspension of50.8 g (0.225 mol) of 2,2-diphenylpropionic acid and 200 mL ofacetonitrile at 20° C. 70.10 g (0.494 mol) of methyl iodide are addeddropwise to the resulting solution within 30 minutes. Then the mixtureis stirred overnight at 20° C. The solvent is evaporated down, theresidue is extracted with diethylether/water, the organic phase iswashed with water, dried over Na₂SO₄, and evaporated to dryness. Yield:48.29 g of viscous residue 3.1. (89% of theory).

[0110] 3.2: tropenol 2,2-diphenylpropionate 4c

[0111] 4.80 g (0.02 mol) of methyl 2,2-diphenylpropionate 3b, 2.78 g(0.02 mol) of tropenol, and 0.046 g of sodium are heated as a melt at 75mbar for 4 hours over a bath of boiling water, shaking from time totime. After cooling, the sodium residues are dissolved withacetonitrile, the solution is evaporated to dryness, and the residueextracted with dichloromethane/water. The organic phase is washed withwater, dried over MgSO₄, and evaporated to dryness. From the residue, 4cis precipitated as the hydrochloride and this is recrystallized fromacetone. Yield: 5.13 g (67% of theory); TLC: R_(f) value: 0.28 (eluent:sec-butanol/formic acid/water 75:15:10); melting point: 134° C.-135° C.

[0112] 3.3: tropenol 2,2-diphenylpropionate Methobromide

[0113] 2.20 g (0.006 mol) of 4c are reacted analogously to Example 1,step 1.3. The crystals formed are suction filtered, washed withdichloromethane, dried and then recrystallized frommethanol/diethylether. Yield: 1.84 g (66% of theory); TLC: R_(f) value:0.11 (eluent as in step 1.2); melting point: 222° C.-223° C.;C₂₄H₂₈NO₂xBr (442.4); elemental analysis: calculated: C (65.16), H(6.38), N (3.17); found.: C (65.45), H (6.29), N (3.16).

EXAMPLE 4 Tropenol 2-fluoro-2,2-bis(3,4-difluorophenyl)acetateMethobromide

[0114]

[0115] 4.1.: Ethyl 3,3′, 44′-tetrafluorobenzilate 3c

[0116] The Grignard reagent is prepared from 2.24 g (0.092 mol) ofmagnesium chips, a few granules of iodine, and 17.80 g (0.092 mol) of1-bromo-3,4-difluorobenzene in 100 mL of THF at 50° C. After the halidehas all been added, the mixture is stirred for another hour. TheGrignard reagent thus obtained is added dropwise to 18.81 g (0.088 mol)of ethyl 3,4-difluorophenylglyoxylate in 80 mL of THF at 10° C.-15° C.and the mixture obtained is stirred for 2 hours at 5° C. The whitesuspension is poured onto ice/sulfuric acid for working up, extractedwith ethyl acetate, the organic phase is washed with water, dried overMgSO₄, and evaporated to dryness. The crude product is purified bycolumn chromatography (eluent: toluene). Yield: 10.80 g of oil 4.1. (38%of theory).

[0117] 4.2.: Tropenol 3,3′,4,4′-tetrafluorobenzilate 5b

[0118] 4.27 g (0.013 mol) of ethyl 3,3′,4,4′-tetrafluorobenzilate 3c,1.81 g (0.013 mol) of tropenol and 0.03 g sodium are heated as a melt at75 mbar for 4 hours over a bath of boiling water, shaking from time totime. After cooling, the sodium residues are dissolved withacetonitrile, the solution is evaporated to dryness, and the residueextracted with dichloromethane/water. The organic phase is washed withwater, dried over MgSO₄, and evaporated to dryness. The residueremaining is mixed with diethylether/petroleum ether (1:9), suctionfiltered and washed. Yield: 2.50 g (46% of theory); TLC: R_(f) value:0.29 (eluent: sec-butanol/formic acid/water (75:15:10)); melting point:147° C.-148° C.

[0119] 4.3: tropenol 2-fluoro-2,2-bis(3,4-difluorophenyl)acetate 4d

[0120] 2.66 g (0.012 mol) of bis-(2-methoxyethyl)aminosulfur trifluoridewere placed in 10 mL of dichloromethane and within 20 minutes a solutionof 0.01 mol of 5b in 65 mL of dichloromethane was added dropwise at 15°C.-20° C. The mixture is stirred for 20 hours at ambient temperature,cooled to 0° C. and carefully mixed with 80 mL of water with thoroughstirring. The mixture is then carefully adjusted to pH 8 with aqueousNaHCO₃ solution, the organic phase is separated off, the aqueous phaseis extracted again with dichloromethane, the combined organic phases arewashed with water, dried over MgSO₄, and evaporated to dryness. Thehydrochloride is precipitated and recrystallized fromacetonitrile/diethylether. Yield: 2.60 g of white crystals (57% oftheory); melting point: 233° C.

[0121] 4,4: tropenol 2-fluoro-2,2-bis(3,4-difluorophenyl)acetateMethobromide

[0122] 2,20 g (0.0052 mol) of 4d are reacted analogously to Example 1,step 1.3. The crystals formed are suction filtered, washed withdichloromethane, dried, and then recrystallized frommethanol/diethylether. Yield: 1.95 g (72% of theory); TLC: R_(f) value:0.17 (eluent: nbutanol/water/formic acid (conc.)/acetone/dichloromethane(36:15:15:15:5)); melting point: 247° C.; C₂₃H₂₁F₅NO₂xBr (518.3);elemental analysis: calculated: C (53.30), H (4.08), N (2.70); found: C(53.22), H (4.19), N (2.69).

EXAMPLE 5 Scopine 2,2-diphenylpropionate Ethylbromide

[0123]

[0124] 1.81 g (0.005 mol) of 4a, 35 mL of acetonitrile and 1.64 g (0.015mol) of ethylbromide are combined at 20° C. and left to stand for 3days. The solution is evaporated to dryness and the residuerecrystallized from ethanol. Yield: 1.38 g (58% of theory); meltingpoint: 208° C.-209° C.; TLC: R_(f) value: 0.33 (eluent as in step 1.2);melting point: 210° C.-211° C.; C₂₅H₃₀NO₃xBr (472.42); elementalanalysis: calculated: C (63.56), H (6.40), N (2.96); found: C (63.49), H(6.24), N (2.88).

EXAMPLE 6 Scopine 2-fluoro-2,2-bis(3,4-difluorophenyl)acetateMethobromide

[0125]

[0126] 6.1.: Scopine 3,3′,4,4′-tetrafluorobenzilate 5c

[0127] 3.61 g (0.011 mol) of ethyl 3,3′,4,4′-tetrafluorobenzilate 3c,1.71 g (0.011 mol) of scopine and 0.03 g sodium are heated as a melt at75 mbar over a bath of boiling water for 4 hours, shaking from time totime. After cooling, the sodium residues are dissolved withacetonitrile, the solution is evaporated to dryness and the residueextracted with dichloromethane/water. The organic phase is washed withwater, dried over MgSO₄, and evaporated to dryness. The residueremaining is combined with diethylether/petroleum ether (1:9), suctionfiltered and washed. Yield: 1.75 g (36% of theory); melting point: 178°C.-179° C.

[0128] 6.2: Scopine 2-fluoro-2,2-bis(3,4-difluorophenyl)acetate 4e

[0129] 0.6 mL (0.0033 mol) of bis-(2-methoxyethyl)aminosulfurtrifluoride are reacted with 1.2 g (0.0028 mol) of 5c analogously toExample 4, step 4.3. Yield: 1.15 g of colorless oil (95% of theory).

[0130] 6.3: Scopine 2-fluoro-2,2-bis(3,4-difluorophenyl)acetateMethobromide

[0131] 1.15 g (0.0026 mol) of 4e and 1.5 g (0.0079 mol) of 50% methylbromide solution are reacted analogously to Example 1, step 1.3. Thecrystals formed are suction filtered, washed with dichloromethane,dried, and then recrystallized from acetone. Yield: 0.88 g (63% oftheory); TLC: R_(f) value: 0.27 (eluent: n-butanol/water/formic acid(conc.)/acetone/dichloromethane (36:15:15:15:5)); melting point: 212°C.; C₂₃H₂₁F₅NO₃xBr 15 (535.33).

EXAMPLE 7 Tropenol 2-fluoro-2,2-bis(4-fluorophenyl)acetate Methobromide

[0132]

[0133] 7.1.: Methyl 4,4′-difluorobenzilate 3d

[0134] I.3.1.: 4,4′-difluorobenzilic Acid

[0135] At about 100° C. a solution of 24.62 g (0.1 mol) of4,4′-difluorobenzil in 250 mL of dioxane is added dropwise to a solutionof 49.99 g (1.25 mol) of NaOH flakes in 300 mL of water and stirred for2 h. The dioxane is largely distilled off and the aqueous solutionremaining is extracted with dichloromethane. When the aqueous solutionis acidified with sulfuric acid, a precipitate is formed which issuction filtered, washed and dried. The filtrate is extracted withdichloromethane, the organic phase is dried over Na₂SO₄ and evaporatedto dryness. Yield: 25.01 g (95% of theory); melting point: 133° C.-136°C.

[0136] 7.1.2.: Methyl 4,4′-difluorobenzilate

[0137] 25.0 g (0.095 mol) of 4,4′-difluorobenzilic acid are added tofreshly prepared sodium ethoxide solution containing 2.17 g (0.095 mol)of sodium and 200 mL of ethanol at 20° C. and stirred for 3 h. Thesolution is evaporated to dryness, the residue is dissolved in DMF,22.57 g (0.16 mol) of methyl iodide are added dropwise at 20° C. and themixture is stirred for 24 h. It is worked up and purified analogously tocompound 3b. Yield: 21.06 g of 11 (80% of theory).

[0138] 7.2.: Tropenol 4,4′-difluorobenzilate 5d

[0139] 11.13 g (0.04 mol) of methyl 4,4′-difluorobenzilate 3d and 5.57 g(0.04 mol) of tropenol are reacted with 0.09 g sodium analogously toExample 3, step 3.2. The product is recrystallized from acetonitrile.Yield: 10.43 g (62% of theory); melting point: 233-235° C.

[0140] 7.3: Tropenol 2-fluoro-2,2-bis(4-fluorophenyl)acetate 4f

[0141] 2.94 g (0.013 mol) of bis-(2-methoxyethyl)-aminosulfurtrifluoride are reacted with 3.85 g (0.01 mol) of 5d analogously toExample 4, step 4.3 in 100 mL of dichloromethane. The product isrecrystallized from acetonitrile in the form of its hydrochloride.Yield: 2.93 g (69% of theory).

[0142] 7.4: Tropenol 2-fluoro-2,2-bis(4-fluorophenyl)acetateMethobromide

[0143] 2.6 g (0.0067 mol) of 4f and 1.9 g (0.0079 mol) of 50%methylbromide solution are reacted analogously to Example 1, step 1.3.The crystals formed are suction filtered, washed with dichloromethane,dried and then recrystallized from methanol/diethylether. Yield: 2.82 gof white crystals (87% of theory); TLC: R_(f) value: 0.55 (eluent:according to Example 1, step 1.2); melting point: 230-231° C.;C₂₃H₂₃F₃NO₂xBr (482,34); elemental analysis: calculated: C (57.27), H(4.81), N (2.90); found: C (57.15), H (4.84), N (2.96).

EXAMPLE 8 Scopine 2-fluoro-2,2-bis(4-fluorophenyl)acetate Methobromide

[0144]

[0145] 8.1: scopine 4,4′-difluorobenzilate 5e

[0146] 4.22 g (0.01 mol) of tropenol 4,4′-difluorobenzilate 5d aresuspended in 80 mL of DMF. At an internal temperature of about 40° C., asolution of 2.57 g (0.0273 mol) of H₂O₂-urea in 20 mL of water, togetherwith 0.2 g (0.0011 mol) of vanadium (V) oxide is added and the resultingmixture is stirred for 4.5 hours at 60° C. After cooling to 20° C., theprecipitate formed is suction filtered, the filtrate is adjusted to pH 3with 4 N hydrochloric acid and combined with Na₂S₂O₅ dissolved in water.The resulting green solution is evaporated to dryness and the residue isextracted with dichloromethane/water. The acidic aqueous phase is madebasic with Na₂CO₃, extracted with dichloromethane, and the organic phaseis dried over Na₂SO₄ and concentrated. Then 0.5 mL of acetyl chloride isadded at about 15° C. and stirred for 1.5 hours. After extraction with0.1 N hydrochloric acid, the aqueous phase is made basic, extracted withdichloromethane, the organic phase is dried over Na₂SO₄, and evaporatedto dryness. The hydrochloride is precipitated from the residue andrecrystallized from methanol/diethylether. Yield: 3.61 g of whitecrystals (78% of theory); melting point: 243° C.-244° C.

[0147] 8.2: Scopine 2-fluoro-2,2-bis(4-fluorophenyl)acetate 4 g

[0148] 1.48 g (0.0067 mol) of bis-(2-methoxyethyl)aminosulfurtrifluoride are reacted with 2.0 g (0.005 mol) of 5e analogously toExample 4, step 4.3 in 80 mL of dichloromethane. The product isrecrystallized from ethanol in the form of its hydrochloride. Yield:2.07 g (94% of theory); melting point: 238° C.-239° C.

[0149] 8.3: scopine 2-fluoro-2,2-bis(4-fluorophenyl)acetate Methobromide

[0150] 1.6 g (0.004 mol) of 4g and 1.14 g (0.0079 mol) of 50%methylbromide solution are reacted analogously to Example 1, step 1.3.The crystals formed are suction filtered, washed with dichloromethane,dried and then recrystallized from acetonitrile. Yield: 1.65 g of whitecrystals (61% of theory); TLC: R_(f) value: 0.25 (eluent: according toExample 1, step 1.2); melting point: 213° C.-214° C.; C₂₃H₂₃F₃NO₃xBr(498.34); elemental analysis: calculated: C (55.43), H (4.65), N (2.81);found: C (54.46), H (4.67), N (2.80).

EXAMPLE 9 Tropenol 2-fluoro-2,2-diphenylacetate Methobromide

[0151]

[0152] 9.1.: Tropenol Benzilate 5f

[0153] Tropenol benzilate and processes for preparing it are known fromWO 92/16528.

[0154] 9.2: tropenol 2-fluoro-2.2-diphenylacetate 4h 15.86 mL (0.086mol) of bis-(2-methoxyethyl)aminosulfur trifluoride is reacted with 25 g(0.072 mol) of 5f analogously to Example 4, step 4.3 in 480 mL ofchloroform. The product is recrystallized from acetone in the form ofits hydrochloride. Yield: 18.6 g of white crystals (67% of theory);melting point: 181° C.-182° C.

[0155] 9.3: Tropenol 2-fluoro-2.2-diphenylacetate Methobromide

[0156] 11.12 g (0.032 mol) of 4h and 18.23 g (0.096 mol) of 50%methylbromide solution are reacted analogously to Example 1, step 1.3.The crystals formed are recrystallized from acetonitrile. Yield: 11.91 gof white crystals (83% of theory); TLC: R_(f) value: 0.4 (eluent:according to Example 4, step 4.4); melting point: 238° C.-239° C.;C₂₃H₂₅FNO₂xBr (446.36); elemental analysis: calculated: C (61.89), H(5.65), N (3.14); found: C (62.04), H (5.62), N (3.17).

EXAMPLE 10 Tropenol 2-fluoro-2,2-(3-chlorophenyl)acetate Methobromide

[0157]

[0158] 10.1.: Methyl 3,3′-dichlorobenzilate 3e

[0159] 10.1.1.: 3,3′-dichlorobenzil

[0160] 100 mL of ethanol is used at ambient temperature and 50.0 g(0.356 mol) of 3-chlorobenzaldehyde and 4.54 g (0.018 mol) of3-ethyl-5-(2-hydroxyethyl)-4methylthiazolium bromide are added. Then10.7 g (0.11 mol) of triethylamine are added dropwise. The mixture isrefluxed for 3 hours and evaporated to dryness. The residue is taken upin ethyl acetate and extracted with water, sodium pyrosulfite in water,and Na₂CO₃ solution. After drying over MgSO₄, it is evaporated todryness. The product obtained is recrystallized from isopropanol andpetroleum ether. Yield: 13.2 g of white crystals (13% of theory);melting point: 69° C.-70° C.

[0161] 13.0 g of the acyloin thus obtained is dissolved in 460 mLacetonitrile at room temperature (RT), 0.0867 g of vanadium (V)oxytrichloride are added and oxygen is piped in. After 1.5 hours, thesolution is evaporated to dryness, extracted with ethyl acetate andwater, as well as Na₂CO₃ solution, dried over MgSO₄, and evaporated todryness. The residue remaining is stirred with petroleum ether/ethylacetate (95:5). Yield: 12.59 g of yellow crystals (97% of theory);melting point: 116° C.-117° C.

[0162] 10.1.2.: 3,3′-dichlorobenzilic Acid

[0163] 51.45 g (1.286 mol) of sodium hydroxide in 1000 mL water isplaced in a bath of boiling water with thorough stirring and a solutionof 28.5 g (0.102 mol) of 3,3′-dichlorobenzil in 700 mL dioxane is addeddropwise and then stirred for another 1 hour. After cooling, the dioxaneis evaporated down, the residue is diluted with water and extracted withdiethylether. The organic phase is acidified, extracted withdichloromethane, dried over MgSO₄, and evaporated to dryness. Yield:32.7 g (71% of theory).

[0164] 10.1.3.: Methyl 3,3′-dichlorobenzilate

[0165] From 100 mL of ethanol and 1.97 g (0.0855 mol) of sodium, asodium ethoxide solution is prepared to which 26.6 g (0.0855 mol) of3,3′-dichlorobenzilic acid in 50 mL of ethanol are added dropwise. Themixture is then stirred for 4 hours at ambient temperature. After thesolvent has been distilled off, the residue is dissolved in 150 mL DMFand 24.27 g (0.171 mol) of methyl iodide are added dropwise, thenstirred for another 24 hours. While cooling with ice, 300 mL of waterand 200 mL of diethylether are added dropwise, the phases are separated,the aqueous phase is extracted with diethylether, then the organicphases are washed with Na₂CO₃ solution and shaken with water untilneutral. After drying over Na₂SO₄, the mixture is evaporated to dryness.Yield: 22.91 g of yellow oil (82% of theory).

[0166] 10.2.: Tropenol 3,3′-dichlorobenzilate 5g

[0167] 22.9 g (0.074 mol) of methyl 3,3′-dichlorobenzilate 3e, 15.37 g(0.11 mol) of tropenol and 0.17 g of sodium are heated for 4 hours as amelt over a bath of boiling water at 75 mbar with occasional shaking.After cooling, the sodium residues are dissolved with acetonitrile, thesolution is evaporated to dryness, and the residue is extracted withdichloromethane/water. The organic phase is washed with water, driedover MgSO₄, and evaporated to dryness. The product is recrystallizedfrom acetonitrile in the form of its hydrochloride. Yield: 16.83 g ofwhite crystals (50% of theory); melting point: 184° C.-185° C.

[0168] 10.3: Tropenol 2-fluoro-2,2-bis(3-chlorophenyl)acetate 4i

[0169] 1.48 g (0.0067 mol) of bis-(2-methoxyethyl)aminosulfurtrifluoride is used in 10 mL of dichloromethane and within 20 minutes at15° C.-20° C., a solution of 2.09 g of 5g in 65 mL of dichloromethane isadded dropwise. The mixture is stirred for 20 hours at ambienttemperature, cooled to 0° C., and carefully combined with 80 mL of waterwith thorough stirring. The mixture is then carefully adjusted to pH 8with aqueous NaHCO₃ solution, the organic phase is separated off, theaqueous phase is again extracted with dichloromethane, the combinedorganic phases are washed with water, dried over MgSO₄, and evaporatedto dryness. The hydrochloride is precipitated and recrystallized fromacetonitrile/diethylether.

[0170] Yield: 1.20 g of white crystals (53% of theory); melting point:136° C.-137° C.

[0171] 10.4: Tropenol 2-fluoro-2,2-bis(3-chlorophenyl)acetateMethobromide

[0172] 1.0 g (0.002 mol) of 4h are reacted analogously to Example 1,step 1.3. The crystals formed are suction filtered, washed withdichloromethane, dried and then recrystallized frommethanol/diethylether. Yield: 0.82 g of white crystals (80% of theory);TLC: Rf value: 0.14 (eluent: n-butanol/water/formicacid(conc.)/acetone/dichloromethane (36:15:15:15:5)); melting point:180° C.-181° C.; C₂₃H₂₃Cl₂FNO₂xBr (515.25).

[0173] As has been found, the compounds of general formula 1 arecharacterized by their versatility in therapeutic use. Particularmention should be made of those applications for which the compounds offormula 1 according to the invention are preferably used on the basis oftheir pharmaceutical activity as anticholinergic agents. These include,for example, the treatment of asthma or chronic obstructive pulmonarydisease COPD). The compounds of general formula 1 may also be used totreat vagally induced sinus bradycardia and to treat heart rhythmdisorders. In general, the compounds according to the invention may alsobe used to treat spasms, e.g., in the gastrointestinal tract, withtherapeutic benefit. They may also be used in the treatment of spasms inthe urinary tract and in menstrual disorders, for example. Of the rangesof indications mentioned above, the treatment of asthma and COPD usingthe compounds of formula 1 according to the invention is of particularimportance.

[0174] The compounds of general formula 1 may be used on their own orcombined with other active substances of formula 1 according to theinvention.

[0175] The compounds of general formula 1 may optionally also becombined with other pharmacologically active substances. These include,in particular, betamimetics, antiallergic agents, PAF-antagonists,leukotriene-antagonists, and corticosteroids and combinations of theseactive substances.

[0176] Examples of betamimetics which may be used in conjunction withthe compounds of formula 1 according to the invention include compoundsselected from among bambuterol, bitolterol, carbuterol, clenbuterol,fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol,reproterol, salmeterol, sulfonterol, terbutaline, tulobuterol,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol,and1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol,optionally in the form of their racemates, their enantiomers, theirdiastereomers, as well as optionally their pharmacologically acceptableacid addition salts and hydrates. It is particularly preferable to use,as betamimetics, active substances of this kind, combined with thecompounds of formula 1 according to the invention, selected from amongfenoterol, formoterol, salmeterol,1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,optionally in the form of their racemates, their enantiomers, theirdiastereomers, as well as optionally their pharmacologically acceptableacid addition salts and hydrates. Of the betamimetics mentioned above,the compounds formoterol and salmeterol, optionally in the form of theirracemates, their enantiomers, their diastereomers, as well as optionallytheir pharmacologically acceptable acid addition salts and hydrates, areparticularly important.

[0177] The acid addition salts of the betamimetics selected from amongthe hydrochloride, hydrobromide, sulfate, phosphate, fumarate,methanesulfonate and xinafoate are preferred according to the invention.In the case of salmeterol, the salts selected from among thehydrochloride, sulfate and xinafoate are particularly preferred,especially the sulfates and xinafoates. Of outstanding importanceaccording to the invention are salmeterol×½H₂SO₄ and salmeterolxinafoate. In the case of formoterol, the salts selected from among thehydrochloride, sulfate and fumarate are particularly preferred,especially the hydrochloride and fumarate. Of outstanding importanceaccording to the invention is formoterol fumarate.

[0178] Within the scope of the present invention, the termcorticosteroids, which may optionally be used in conjunction with thecompounds of formula 1, denotes compounds selected from amongflunisolide, beclomethasone, triamcinolone, budesonide, fluticasone,mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 anddexamethasone. The preferred corticosteroids within the scope of thepresent invention are those selected from among flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, and dexamethasone, while budesonide, fluticasone,mometasone, and ciclesonide, especially budesonide and fluticasone, areof particular importance. The term steroids may be used on its own,within the scope of the present patent application, instead of the termcorticosteroids. Any reference to steroids within the scope of thepresent invention also includes a reference to salts or derivativeswhich may be formed from the steroids. Examples of possible salts orderivatives include: sodium salts, sulfobenzoates, phosphates,isonicotinates, acetates, propionates, dihydrogen phosphates,palmitates, pivalates, or furoates. The corticosteroids may optionallyalso be in the form of their hydrates.

[0179] Within the scope of the present invention, the term dopamineagonists, which may optionally be used in conjunction with the compoundsof formula 1, denotes compounds selected from among bromocriptine,cabergolin, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol,roxindole, ropinirole, talipexole, terguride, and viozan. It ispreferable within the scope of the present invention to use, ascombination partners with the compounds of formula 1, dopamine agonistsselected from among pramipexol, talipexole and viozan, pramipexol beingof particular importance. Any reference to the abovementioned dopamineagonists also includes, within the scope of the present invention, areference to any pharmacologically acceptable acid addition salts andhydrates thereof which may exist. By the physiologically acceptable acidaddition salts thereof which may be formed by the abovementioneddopamine agonists are meant, for example, pharmaceutically acceptablesalts selected from among the salts of hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid,fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid,and maleic acid.

[0180] Examples of antiallergic agents which may be used according tothe invention as a combination with the compounds of formula 1 includeepinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifene, emedastine, dimetindene,clemastine, bamipine, hexachloropheniramine, pheniramine, doxy]amine,chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, desloratadine, and meclizine. Preferred antiallergic agentswhich may be used within the scope of the present invention incombination with the compounds of formula 1 according to the inventionare selected from among epinastine, cetirizine, azelastine,fexofenadine, levocabastine, loratadine, ebastine, desloratadine andmizolastine, epinastine, and desloratadine being particularly preferred.Any reference to the above-mentioned antiallergic agents also includes,within the scope of the present invention, a reference to anypharmacologically acceptable acid addition salts thereof which mayexist.

[0181] The following are examples of PAF antagonists which may be usedin conjunction with the compounds of formula 1 according to theinvention:4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepineand6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclopenta-[4,5]thieno-[3,2-a][1,2,4]triazolo[4,3-a][1,4]diazepine.

[0182] If the compounds of formula 1 are used in conjunction with otheractive substances, the combination with steroids or betamimetics isparticularly preferred of all the categories of compounds mentionedabove. Combinations with betamimetics, particularly betamimetics havinga long-lasting activity, is of particular importance. The combination ofthe compounds of formula 1 according to the invention with salmeterol orformoterol is particularly preferred, whilst the combination withformoterol is most preferred.

[0183] Suitable preparations for administering the compounds of formula1 include tablets, capsules, suppositories, solutions, etc. Ofparticular importance according to the invention (particularly whentreating asthma or COPD) is the administration of the compoundsaccording to the invention by inhalation. The proportion ofpharmaceutically active compound or compounds should be in the rangefrom 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the totalcomposition. Suitable tablets may be obtained, for example, by mixingthe active substance(s) with known excipients, for example, inertdiluents such as calcium carbonate, calcium phosphate, or lactose,disintegrants such as corn starch or alginic acid, binders such asstarch or gelatine, lubricants such as magnesium stearate or talc and/oragents for delaying release, such as carboxymethyl cellulose, celluloseacetate phthalate, or polyvinyl acetate. The tablets may also compriseseveral layers.

[0184] Coated tablets may be prepared accordingly by coating coresproduced analogously to the tablets with substances normally used fortablet coatings, for example, collidone or shellac, gum arabic, talc,titanium dioxide, or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

[0185] Syrups or elixirs containing the active substances orcombinations thereof according to the invention may additionally containa sweetener such as saccharine, cyclamate, glycerol, or sugar and aflavor enhancer, e.g., a flavoring such as vanillin or orange extract.They may also contain suspension adjuvants or thickeners such as sodiumcarboxymethyl cellulose, wetting agents such as, for example,condensation products of fatty alcohols with ethylene oxide, orpreservatives such as p-hydroxybenzoates.

[0186] Solutions are prepared in the usual way, e.g., with the additionof isotonic agents, preservatives such as p-hydroxybenzoates, orstabilizers such as alkali metal salts of ethylenediamine tetraaceticacid, optionally using emulsifiers and/or dispersants, whilst if wateris used as the diluent, for example, optionally organic solvents mayoptionally be used as solvating agents or dissolving aids, andtransferred into injection vials or ampoules or infusion bottles.

[0187] Capsules containing one or more active substances or combinationsof active substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules. Suitable suppositories may be made, forexample, by mixing with carriers provided for this purpose, such asneutral fats or polyethyleneglycol or the derivatives thereof.Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.,petroleum fractions), vegetable oils (e.g., groundnut or sesame oil),mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carrierssuch as, e.g., natural mineral powders (e.g., kaolins, clays, talc, andchalk), synthetic mineral powders (e.g., highly dispersed silicic acidand silicates), sugars (e.g., cane sugar, lactose, and glucose),emulsifiers (e.g., lignin, spent sulfite liquors, methylcellulose,starch, and polyvinylpyrrolidone) and lubricants (e.g., magnesiumstearate, talc, stearic acid, and sodium lauryl sulfate).

[0188] The preparations are administered by the usual methods,preferably by inhalation in the treatment of asthma or COPD. For oraladministration the tablets may, of course, contain, apart from theabovementioned carriers, additives such as sodium citrate, calciumcarbonate, and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine, and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulfate, and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavor enhancers or colorings in addition to the excipients mentionedabove.

[0189] The dosage of the compounds according to the invention isnaturally greatly dependent on the route of administration and thecomplaint to be treated. When administered by inhalation, the compoundsof formula 1 are characterized by high efficacy even at doses in the μgrange. The compounds of formula 1 can also be used effectively above theμg range. The dosage may then be in the gram range, for example.Particularly when administered by a method other than inhalation, thecompounds according to the invention may be given in higher doses (inthe range from 1 to 1000 mg, for example, although this does not implyany limitation).

[0190] The examples of formulations which follow illustrate the presentinvention without restricting its scope:

EXAMPLES OF PHARMACEUTICAL FORMULATIONS

[0191] A. Tablets per tablet active substance 100 mg lactose 140 mg cornstarch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg

[0192] The finely ground active substance, lactose and some of the cornstarch are mixed together. The mixture is screened, then moistened witha solution of polyvinylpyrrolidone in water, kneaded, wet-granulated,and dried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size. B. Tablets per Tablet activesubstance 80 mg lactose 55 mg corn starch 190 mg microcrystallinecellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch23 mg magnesium stearate 2 mg 400 mg

[0193] The finely ground active substance, some of the corn starch,lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixedtogether, the mixture is screened and worked with the remaining cornstarch and water to form a granulate which is dried and screened. Thesodium carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize. C. Ampoule Solution active substance 50 mg sodium chloride 50 mgwater for inj. 5 mL

[0194] The active substance is dissolved in water at its own pH oroptionally at pH 5.5 to 6.5 and sodium chloride is added to make itisotonic. The solution obtained is filtered free from pyrogens and thefiltrate is transferred under aseptic conditions into ampoules which arethen sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg,and 50 mg of active substance. D. Metering Aerosol Active substance0.005 Sorbitan trioleate 0.1 Monofluorotrichloromethane anddifluorodichloromethane (2:3) ad 100

[0195] The suspension is transferred into a conventional aerosolcontainer with a metering valve. Preferably, 50 μl of suspension aredelivered per spray. The active substance may also be metered in higherdoses if desired (e.g., 0.02% by weight). E. Solutions (in mg/100 mL)Active substance 333.3 mg Formoterol fumarate 333.3 mg Benzalkoniumchloride  10.0 mg EDTA  50.0 mg HCl (1 N) ad pH 3.4

[0196] This solution may be prepared in the usual manner. F. Powder forInhalation Active substance 6 μg Formoterol fumarate 6 μg Lactosemonohydrate ad 25 mg

[0197] The powder for inhalation is produced in the usual way by mixingthe individual ingredients together. G. Powder for inhalation Activesubstance 10 μg Lactose monohydrate ad 5 mg

[0198] The powder for inhalation is produced in the usual way by mixingthe individual ingredients together.

We claim:
 1. A compound of formula 1

wherein: A is —CH₂—CH₂—; X⁻ is an anion with a single negative charge;R¹ and R², which are identical or different, are each C₁-C₄-alkyl, whichare optionally substituted by hydroxy or halogen; R³, R⁴, R⁵, and R⁶,which are identical or different, are each hydrogen, C₁-C₄-alkyl,C₁-C₄alkyloxy, hydroxy, CF₃, CN, NO₂, or halogen; and R⁷ is C₁-C₄-alkyl,C₁-C₄-alkyloxy, C₁-C₄-alkylene-halogen, halogen-C₁-C₄-alkyloxy,C₁-C₄-alkylene-OH, CF₃, —C₁-C₄-alkylene-C₁-C₄-alkyloxy,—O—COC₁-C₄-alkyl, —O—COC₁-C₄-alkyl-halogen, —O—COCF₃, or halogen.
 2. Thecompound of formula 1 according to claim 1, wherein: X⁻ is an anion witha single negative charge selected from chloride, bromide, methylsulfate,4-toluenesulfonate, and methanesulfonate; R¹ and R², which are identicalor different, are each a group selected from methyl, ethyl, n-propyl,and isopropyl, which are optionally substituted by hydroxy or fluorine;R³, R⁴, R⁵, and R⁶, which are identical or different, are each hydrogen,methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine,bromine, CN, CF₃, or NO₂; and R⁷ is methyl, ethyl, methyloxy, ethyloxy,—CH₂—F, —CH₂—CH₂—F, —O—CH₂—F, —O—CH₂—CH₂—F, —CH₂—OH, —CH₂—CH₂—OH, CF₃,—CH₂—OMe, —CH₂—CH₂—OMe, —CH₂—OEt, —CH₂—CH₂OEt, —O—COMe, —O—COEt,—O—COCF₃, —O—COCF₃, fluorine, chlorine, or bromine.
 3. The compound offormula 1, according to claim 2, wherein: X⁻ is an anion with a singlenegative charge selected from chloride, bromide, and methanesulfonate;R¹ and R², which are identical or different, are each methyl or ethyl,which are optionally substituted by hydroxy or fluorine; R³, R⁴, R⁵, andR⁶, which are identical or different, are each hydrogen, methyl, ethyl,methyloxy, ethyloxy, hydroxy, fluorine, chlorine, or bromine; and R⁷ ismethyl, ethyl, methyloxy, ethyloxy, CF₃, or fluorine.
 4. The compound offormula 1, according to claim 3, wherein: X⁻ is bromide; R¹ and R²,which are identical or different, are each methyl or ethyl; R³, R⁴, R⁵,and R⁶, which are identical or different, are each hydrogen, methyl,methyloxy, chlorine, or fluorine; and R⁷ is methyl or fluorine.
 5. Thecompound of formula 1, according to claim 4, wherein: X⁻ is bromide; R¹and R², which are identical or different, are each methyl or ethyl; R³,R⁴, R⁵, and R⁶, which are identical or different, denote hydrogen orfluorine; and R⁷ is methyl or fluorine.
 6. A method of treating adisease that is responsive to anticholinergic activity, comprisingadministering to a host in need thereof an effective amount of acompound of formula 1 according to one of claims 1 to
 5. 7. A methodaccording to claim 6, wherein the disease is selected from asthma, COPD,vagally induced sinus bradycardia, heart rhythm disorders, spasms in thegastrointestinal tract, spasms in the urinary tract, and menstrualdisorders.
 8. A pharmaceutical composition comprising one or morecompounds of formula 1 according to one of claims 1 to 5, or aphysiologically acceptable salt thereof, optionally together with one ormore conventional excipients and/or carriers.
 9. A pharmaceuticalcomposition according to claim 8, further comprising at least oneadditional active substance selected from the group consisting of:betamimetics, antiallergic agents, PAF-antagonists,leukotriene-antagonists, and steroids.
 10. A process for preparing acompound of formula 1 according to claim 1

wherein A, X⁻ and R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ have the meanings givenin claim 1, characterised in that a compound of formula 3

wherein R³, R⁴, R⁵, R⁶, and R⁷ have the meanings given in claim 1, and Ris chlorine or a C₁-C₄-alkyloxy, is reacted with a compound of formula 2

wherein A and R¹ have the meanings given in claim 1, to obtain acompound of formula 4

wherein A and R¹, R³, R⁴, R⁵, R⁶, and R⁷ have the meanings given inclaim 1, and the compound of formula 4 is then quaternized by reactingit with a compound R²—X, wherein R² and X have the meanings given inclaim 1, to obtain a compound of formula
 1. 11. A compound of formula 4

wherein: A is —CH₂—CH₂—; X⁻ is an anion with a single negative charge;R¹ and R², which are identical or different, are each C₁-C₄-alkyl, whichare optionally substituted by hydroxy or halogen; R³, R⁴, R⁵, and R⁶,which are identical or different, are each hydrogen, C₁-C₄-alkyl,C₁-C₄alkyloxy, hydroxy, CF₃, CN, NO₂, or halogen; and R⁷ is C₁-C₄-alkyl,C₁-C₄-alkyloxy, C₁-C₄-alkylene-halogen, halogen-C₁-C₄-alkyloxy,C¹-C₄-alkylene-OH, CF₃, —C₁-C₄-alkylene-C₁-C₄-alkyloxy,—O—COC₁-C₄-alkyl, —O—COC₁-C₄-alkyl-halogen, —O—COCF₃, or halogen.